Mechanisms of Fibrin Action in Neuronal Functions

纤维蛋白在神经元功能中的作用机制

基本信息

批准号：
8715494
负责人：
Katerina Akassoglou
金额：
$ 28.65万
依托单位：
J. DAVID GLADSTONE INSTITUTES
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-15 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8715494
关键词：
Affect Animal Model Attenuated Binding Blood - brain barrier anatomy Blood Proteins Blood Vessels Blood coagulation Brain Cells Cognitive Cognitive deficits Data Dendrites Dendritic Spines Deposition Disease Event Experimental Designs Extravasation Fibrin Fibrinogen Functional disorder Genetic Goals HIV HIV Encephalopathy Hemorrhage Human ITGAM gene ITGB2 gene Image Immune response Impaired cognition Inflammation Inflammatory Injection of therapeutic agent Injury Integrins Intervention Ischemia Knockout Mice Lasers Life Link Mediating Memory impairment Microglia Microscopy Modeling Molecular Multiple Sclerosis Mus Natural Immunity Nerve Degeneration Nervous system structure Neuraxis Neurodegenerative Disorders Neurologic Neurologic Dysfunctions Neuronal Dysfunction Neurons Paralysed Pathogenesis Pathology Pathway interactions Patients Permeability Plasma Play Process Protocols documentation Regulation Risk Risk Factors Role Rupture Schizophrenia Signal Transduction Spinal Cord Stroke Study models Testing Therapeutic Time Transgenic Mice Traumatic Brain Injury Vertebral column Work cerebrovascular density dentate gyrus design drug efficacy drug testing immune activation in vivo memory recall molecular pathology nervous system disorder neuroinflammation neuron loss neurotoxicity normal aging novel pharmacodynamic model promoter public health relevance receptor repaired response therapeutic development two-photon

项目摘要

DESCRIPTION (provided by applicant): Patients with central nervous system pathologies, including multiple sclerosis, stroke, spinal cord and traumatic injuries, often present with cognitive impairment, indicative of neuronal dysfunction. Although vascular damage and blood-brain barrier (BBB) disruption, which results in leakage of blood proteins into the brain parenchyma, are hallmarks of cognitive pathologies, the molecular links between BBB disruption and neuronal dysfunction remain poorly understtod. We have shown that CNS deposition of fibrinogen, a critical component of blood coagulation, is not merely a marker of BBB disruption, but plays a causative role in the regulation of inflammation and repair in the CNS by activating integrin receptors expressed in nervous system cells. Our long-term goal is to characterize the molecular pathways that are responsible for the effects of fibrinogen in nervous system pathogenesis, as a prerequisite for the development of therapeutic protocols that can specifically target the interactions between fibrinogen and its receptors and attenuate neuropathological disease processes. Our major hypothesis is that fibrinogen activates the CNS innate immune response to induce spine alterations and cognitive deficits in nervous system pathology. Our preliminary data demonstrate that a) stereotactic injection of fibrinogen into the dentate gyrus induces microglial activation and impairs memory recall, b) injection of fibrinogen induces neuronal loss, dendrite retraction and dendritic spine density reduction in mice as shown with in vivo two-photon microscopy, and c) genetic depletion of the CD11b/CD18 microglial receptor rescues fibrinogen-induced spine elimination and dendritic retraction. Our specific aims are designed to test our working model, in which fibrinogen, deposited in the brain following BBB disruption and cerebrovascular abnormalities, activates the innate immune response and causes spine elimination and cognitive decline. We employ a cutting edge experimental design that includes in vivo two-photon imaging of neurons in transgenic mice expressing YFP under Thy1 promoter, following the dynamic interactions between microglial and spines over time in the living mouse, and pharmacologic and genetic inhibition of innate immune activation, including specific inhibition of fibrinogen interactions with CD11b that do not affects its beneficial functions in blood coagulation. Identifying the molecular interplay between fibrinogen following BBB disruption, activation of innate immunity, and neurotoxicity could potentially provide specific targets for pharmacological intervention in a variety of diseases characterized by cerebrovascular abnormalities or increased BBB permeability and cognitive impairment.

描述（由申请人提供）：患有中枢神经系统病理的患者，包括多发性硬化症，中风，脊髓和创伤性损伤，通常出现认知障碍，表明神经元功能障碍。尽管血管损伤和血脑屏障（BBB）破坏导致血液蛋白泄漏到脑实质中，这是认知病理的标志，但BBB破坏与神经元功能障碍之间的分子联系仍然不足。我们已经表明，纤维蛋白原的中枢神经系统沉积（血液凝结的关键成分）不仅是BBB破坏的标志物，而且通过激活在神经系统细胞中表达的整合蛋白受体在CNS的炎症和修复中起病原作用。我们的长期目标是表征负责纤维蛋白原在神经系统发病机理中影响的分子途径，这是开发治疗方案的先决条件，这些方案可以专门针对纤维蛋白原及其受体之间的相互作用并减弱神经病理病理病过程。我们的主要假设是，纤维蛋白原激活了CNS先天免疫反应，以诱导脊柱改变和神经系统病理学的认知缺陷。 Our preliminary data demonstrate that a) stereotactic injection of fibrinogen into the dentate gyrus induces microglial activation and impairs memory recall, b) injection of fibrinogen induces neuronal loss, dendrite retraction and dendritic spine density reduction in mice as shown with in vivo two-photon microscopy, and c) genetic depletion of the CD11b/CD18小胶质细胞受体挽救了纤维蛋白原诱导的脊柱消除和树突缩。我们的具体目的旨在测试我们的工作模型，其中BBB破坏和脑血管异常后沉积在大脑中的纤维蛋白原会激活先天的免疫反应并导致脊柱消除和认知能力下降。我们采用尖端实验设计，包括在Thy1启动子下表达YFP的转基因小鼠中神经元的体内两光子成像，这是在活着的小鼠中的小胶质细胞和刺之间的动态相互作用，以及药理学和遗传抑制与先天性免疫激活的药理和遗传抑制，包括对纤维蛋白的互动的特定抑制作用。在BBB破坏，先天免疫的激活和神经毒性之后，识别纤维蛋白原之间的分子相互作用可能会为各种以脑持久性异常或BBB持久性和认知障碍增加的疾病提供特定的药理干预措施。